Departments of Obstetrics and Gynecology (S.S., M.I., K.S., H.H., M.K.S., Y.N.), Anatomy (Y.A.), and Biochemistry (S.N.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Obstetrics and Gynecology (Y.Y.), Keio University School of Medicine, Shinanomachi, Tokyo, 160-8582, Japan; and Mitsubishi Pharma Corporation (M.U.), Aoba-Ku, Yokohama 227-0033, Japan
Address all correspondence and requests for reprints to: Shigetatsu Shiokawa, M.D., Ph.D., Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka City, Tokyo 181-8611, Japan. E-mail: shiochan{at}kyorin-u.ac.jp.
Abstract
The small guanosine triphosphatase Rho controls cell adhesionand motility through reorganization of the actin cyto-skeletonand regulation of actomyosin contractility. Among the putativetarget molecules of Rho, a Rho-associated coiled coil-formingprotein kinase (ROCK) is thought to participate in Rho-mediatedcell adhesion and motility. In the present study, we exploredthe expression and function of RhoA and ROCK in human trophoblastcells. The colocalization of RhoA, cytokeratin 8/18, and cytokeratin7 in some cells located in the decidual stromal region indicatedthat extravillous trophoblast cells expressed RhoA. In doublestaining for RhoA and ROCK in human chorionic villi, RhoA stainingwas strongly positive in the cytoplasm of cytotrophoblasts,whereas ROCK stained in the cytoplasm of cytotrophoblasts andsyncytiotrophoblasts. Both RhoA and ROCK were stained in cytoplasmaof cultured human cytotrophoblast. Cultured human trophoblastcells contained actin stress fibers that were lost after treatmentwith C3, an exoenzyme produced by Clostridium botulinum. Y-27632,a selective ROCK inhibitor, suppressed RhoA-induced formationof actin stress fibers and formation of focal contact in trophoblastcells. The trophoblast reacquired actin stress fibers and focalcontact after withdrawal of Y-27632. Cultured human cytotrophoblastcells from 7–9 wk of gestation migrated into a fibronectin-coatedmembrane. Both C3 exoenzyme and Y-27632 inhibited cytotrophoblastmigration in a dose-dependent manner. In conclusion, cyto-trophoblastsexpress RhoA and ROCK in their cytoplasm, and RhoA-ROCK is involvedin their assembly of actin stress fibers. Suppression of RhoA-ROCKreduces trophoblast migration. These findings suggest that RhoA-ROCKsignaling is a key regulator of trophoblast cell migration.
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